Inhibitors of Trypanosoma cruzi trypanothione reductase revealed by virtual screening and parallel synthesis.

Abstract

In an approach to discover new inhibitors of trypanothione reductase from Trypanosoma cruzi, the causative agent of Chagas' disease, a virtual high-throughput screening was performed. Two structurally new types of inhibitors emerged, the antimicrobial chlorhexidine {1,1'-hexamethylenebis[5-(4-chlorophenyl)biguanide]}, a linear competitive inhibitor (K(i) = 2 +/- 1 microM), and a piperidine derivative acting as mixed inhibitor (K(i) = 6.2 +/- 2 microM and K(i)' = 8.5 +/- 2 microM). Neither compound interferes with human glutathione reductase. Based on chlorhexidine, different series of compounds were synthesized and studied as inhibitors of T. cruzi trypanothione reductase. Most efficient derivatives were three bis(amidines) showing mixed type inhibition with K(i,slope) and K(i,int) values of 2-5 microM and 16-47 microM, respectively. Although these compounds did not exert an improved inhibitory potency compared to chlorhexidine, the change from competitive to mixed-type inhibition is advantageous, since substrate accumulation does not overcome inhibition. Remarkably, all three derivatives carried two copies of an identical 2-methoxy-4-methyl-1-(phenylmethoxy)benzene substituent.

• Authors: Svea Meiering, Oliver Inhoff, Jan Mies, Adam Vincek, Gabriel Garcia, Bernd Kramer, Matthias Dormeyer, R Luise Krauth-Siegel
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 15 Pg. 4793-802 (Jul 28 2005) ISSN: 0022-2623 [Print] United States
• PMID: 16033259 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amidines
• Piperidines
• NADH, NADPH Oxidoreductases
• trypanothione reductase
• Chlorhexidine

Topics

• Amidines (chemical synthesis, chemistry)
• Animals
• Chlorhexidine (analogs & derivatives, chemical synthesis, chemistry)
• Humans
• Models, Molecular
• NADH, NADPH Oxidoreductases (antagonists & inhibitors, chemistry)
• Piperidines (chemical synthesis, chemistry)
• Structure-Activity Relationship
• Trypanosoma cruzi (enzymology)